Degradation of estrogens, such as ethinyl estradiol, in conventional pharmaceutical products is one of the most critical issues with regard to product shelf life. Stabilization of the estrogen may be achieved by either product packaging in hermetic containers or, more effectively, as in the present invention, by actual stabilization of the pharmaceutical product.
Pharmaceutical products comprising naturally or synthetically derived sex hormones often consist of low dosages of these active ingredients. Given the small amounts of active ingredient required per single dosage, often ranging between 0.1 μg and 500 μg, it is problematic to manufacture unit dosage formulations with reliably consistent amounts of active agent which do not fluctuate within one batch or between batches. Thus, the requirements of content uniformity as set forth by health authorities may not be met.
Moreover, degradation of these small amounts of active ingredient is a further contributor to the fluctuations of the active ingredient in low dosage formulations.
In general, these low dose formulations comprising unstable active agents are problematic in terms of their preparation, storage and use, and there is a need for providing means for stabilization of such formulations.
Complexation of estrogens with cyclodextrins is widely used for improving stability, solubility or bioavailability. For example, EP 0 349 091 discloses compositions containing complexes between 17-β-estradiol and dimethyl-β-cyclodextrin for improving nasal administration, Fridriksdottir et al (Die Pharmazie, vol. 51, 1996, pages 39-42) describes complexes between cyclodextrin and 17-β-estradiol for improving the solubility in aqueous solution so as to improve sublinqual application. Improved solubility is also the focus of U.S. Pat. No. 4,596,795, which relates to a complex between α-, β- and γ-cyclodextrins and derivatives thereof with testosterone, progesterone, and estradiol. U.S. Pat. No. 4,383,992 discloses a water soluble inclusion compound formed by complexing a steroid compound, such as an estrogen with beta-cyclodextrin.
Moreover, U.S. Pat. No. 5,798,338 discloses that the oxidative degradation of 17-α-ethinyl estradiol is reduced upon forming clathrates (complexes) between β-cyclodextrin and 17-α-ethinyl estradiol.
However, although complexation of estrogens with cyclodextrins may solve critical issues with regards to solubility, bioavailability and stability, there are still further problems to solve before complexes between active agents, such as estrogens, and cyclodextrins are suitable for use in pharmaceutical products. Namely, the complexes are prone to dissociation into the free estrogen and the cyclodextrin, particularly upon contact with water. The lack of physical stability of cyclodextrin-estrogen complexes results in significant amounts of free estrogen present in compositions due to, for instance, exposure to aqueous media during the manufacturing process, particularly during granulation. As a consequence, the lifetime of the composition may be decreased due to degradation of free estrogen.
Moreover, the intended improved bioavailability sought by complexing estrogen with cyclodextrin is not achieved due to the lack of physical stability of the cyclodextrin-estrogen complex and the chemical instability of the free estrogen.
Various attempts have been made in order to stabilize compositions comprising complexes between a cyclodextrin and an estrogen. For example, the composition may be stabilized by stabilizing the complex itself. Thus, U.S. Pat. No. 4,727,064 attempts the stabilization of complexes upon using amorphous forms of the complex. Alternatively, complexes may be stabilized and their solubility increased upon adding polymers to the reaction medium upon complexation, as disclosed by Loftsson et al. (Int. J. Pharmaceutics, Vol. 110, 1994, pp169-177). EP 0579435 also discloses complexes between estradiol and cyclodextrins wherein the addition of polymers to the reaction medium increases the stability constant of the complex.
The compositions may also be stabilized upon avoiding a granulation step in the manufacturing process of the composition, as disclosed in WO 00/21570.
There is a need in the art for processes for preparing physically stable complexes of cyclodextrin and estrogen and for compositions, which improve the stability of both the complex and the free estrogen. There is furthermore a need in the art for granulate formulations which allow for physically stable cyclodextrin-estrogen complexes.